A process for the preparation of 4,4'-bis[cyclo[4.2.0]octa-1(6),2,4-trien-3-ylmethyl]-1,1'-biphenyl

Abstract

This invention discloses a method for preparing 4,4'-bis[cyclo[4.2.0]octyl-1(6),2,4-trien-3-ylmethyl]-1,1'-biphenyl, belonging to the field of chemical synthesis. The method uses 4-bromobenzocyclobutene and 4,4'-biphenyldicarboxaldehyde as raw materials, and completes the process in five steps: Grignardization, coupling, solvent replacement quenching with glacial acetic acid, reduction, and purification. The Grignardization reaction uses a cyclic ether as a solvent and is carried out at 45-60℃ to prepare an aryl Grignard reagent; the coupling reaction is carried out at ≤35℃ to achieve nucleophilic addition of the aryl group to the aldehyde group; after quenching with glacial acetic acid and removing the low-boiling solvent, reduction is completed with iodine granules and hypophosphite at 55-62℃; finally, the target product is obtained by dry loading with silica gel at ≤40℃ and column chromatography in a weakly polar system. The process of this invention is simple and mild, with a completely anhydrous and oxygen-free controllable process. The product has a purity of ≥99%, excellent yield, and is suitable for large-scale production. The obtained product can be used as a monomer for photoelectric anti-corrosion dry film polymer.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, specifically to a method for preparing 4,4'-bis[cyclo[4.2.0]octyl-1(6),2,4-trien-3-ylmethyl]-1,1'-biphenyl. The resulting product can be used as a polymer monomer for photoelectric resist dry film and applied in the field of electronic material modification. Background Technology

[0002] Benzocyclobutene resins are a class of high-performance thermosetting resins. Due to their characteristics such as low dielectric constant, low dielectric loss, no release of small molecules during curing, and excellent mechanical properties, they are widely used in aerospace, electronics, pharmaceutical separation and other fields. In particular, there is a significant demand in the electronic information field, such as integrated circuit chip packaging and copper clad laminate preparation.

[0003] Biphenyl-type benzocyclobutene and its derivatives are important functional materials for benzocyclobutene-type resins. Their nonpolar benzo four-membered ring chemical structure has high reactivity for ring opening upon heating and can undergo addition reactions with dienophiles to prepare highly cross-linked thermosetting polymer materials. These are key basic materials for emerging technology fields such as 5G communication, Internet of Things, and wearable devices.

[0004] 4,4'-Di[cyclo[4.2.0]oct-1(6),2,4-trien-3-ylmethyl]-1,1'-biphenyl, as the core biphenyl-type benzocyclobutene monomer, is of great significance to the development of high-end resin materials in terms of its synthesis and application. However, this compound has a long chain length and high product activity, and is very prone to ring-opening reactions (generating other compounds). Existing preparation methods have problems such as cumbersome steps, harsh reaction conditions, low product yield, poor purity, and difficulty in purification, which seriously limit its industrial production and downstream application expansion. Summary of the Invention

[0005] (a) Technical problems to be solved In view of the above-mentioned defects in the synthesis of 4,4'-bis[cyclo[4.2.0]oct-1(6),2,4-trien-3-ylmethyl]-1,1'-biphenyl in the prior art, this application provides a simple, mild, catalyst-free, and controllable preparation method to achieve efficient preparation of the compound, while improving the yield and purity of the product, reducing the purification difficulty, and meeting the needs of industrial production.

[0006] (ii) The technology of this application includes the following: A method for preparing 4,4'-bis[cyclo[4.2.0]oct-1(6),2,4-trien-3-ylmethyl]-1,1'-biphenyl includes the following steps: S1. Dissolve 4-bromobenzocyclobutene (Br-BCB) in an organic solvent suitable for Grignardization, add magnesium shavings and an initiator, and heat to carry out the Grignardization reaction. The reaction is carried out under anhydrous and oxygen-free conditions, and an intermediate is generated after the reaction. S2. Cool the reaction solution of S1 to 10-30℃, and add a solution containing 4,4'-biphenyldicarboxaldehyde dropwise to carry out the coupling reaction. When adding dropwise, control the temperature rise of the system to not exceed 5℃ (the system temperature should not exceed 35℃ to reduce the side reaction between the solvent and the remaining Grignard reagent) and stir thoroughly. After the dropwise addition is completed, continue stirring for at least 1 hour. S3. Add glacial acetic acid to the reaction solution of S2 to quench and dissolve the reaction solution, and remove solvents with boiling points lower than glacial acetic acid by rotary evaporation (including all low-boiling organic solvents introduced in S1-S2). S4. Iodine granules and hypophosphite were added to the reaction solution of S3 to carry out a reduction reaction to generate the target product. After separation and purification, 4,4'-bis[cyclo[4.2.0]octyl-1(6),2,4-trien-3-ylmethyl]-1,1'-biphenyl was obtained.

[0007] According to a preferred embodiment of the present invention, in S1, the organic solvent is tetrahydrofuran, the reaction temperature is 45-60°C, the reaction process is carried out using oil bath heating (to isolate water vapor and avoid water bath heating), and the reaction time is 1-2 hours, preferably maintained for 0.5-0.6 hours after the reaction liquid stops boiling. More preferably, the reaction temperature is 55°C. Experiments show that when using THF as the solvent, the reaction conditions of 55°C and 1 hour are more conducive to the smooth progress of the reaction, and the purity and yield of the obtained product are better.

[0008] According to a preferred embodiment of the present invention, in S1, the initiator is at least one of bromoethane, dibromoethane, or 1,2-dibromoethane, and the amount of initiator is 5-10% of the mass of Br-BCB.

[0009] According to a preferred embodiment of the present invention, in S1, the molar ratio of Br-BCB to magnesium shavings is 1:1.3-1.7, and the concentration of Br-BCB in THF is 0.5M. More preferably, the molar ratio of Br-BCB to magnesium shavings is 1:1.5; experiments show that when the amount of magnesium shavings is 1.5 times the molar amount of Br-BCB, the purity and yield of the obtained product are better.

[0010] According to a preferred embodiment of the present invention, in S2, the molar ratio of 4,4'-biphenyldicarboxaldehyde to Br-BCB is 1:2.2-2.8. More preferably, the molar ratio of 4,4'-biphenyldicarboxaldehyde to Br-BCB is 1:2.5. Experiments show that when the molar ratio of 4,4'-biphenyldicarboxaldehyde to Br-BCB is 1:2.5, the purity and yield of the product are better.

[0011] According to a preferred embodiment of the present invention, in S2, the solvent of the solution containing 4,4'-biphenyldicarboxaldehyde is at least one of dichloromethane (DCM) and THF; both solvents have low boiling points, are easily displaced, and do not react with Grignard reagents or other intermediates at temperatures <35°C.

[0012] According to a preferred embodiment of the present invention, in step S3, the volume ratio of the added glacial acetic acid to the volume of the reaction solution obtained in step S2 is 1-1.2:1, and the boiling temperature of the remaining reaction solution is controlled at 60°C-95°C during rotary evaporation. This temperature ensures that other solvents introduced by the Grignard reaction in S1 and the coupling reaction in S2 are removed by rotary evaporation while glacial acetic acid is retained, thereby achieving solvent displacement.

[0013] According to a preferred embodiment of the present invention, in S3, negative pressure is applied during rotary evaporation to promote volatilization; under negative pressure, the rotary evaporation temperature can be reduced to achieve the purpose of replacing the low-boiling-point solvent introduced in S1-S2 with glacial acetic acid; the rotary evaporation process also includes: cooling and recovering the vapor of the removed low-boiling-point organic solvent.

[0014] According to a preferred embodiment of the present invention, in S4, the molar ratio of 4,4'-biphenyldicarboxaldehyde, iodine granules, and hypophosphite is 1:0.3-0.5:1.5-4; the reaction temperature of the reduction reaction is 55-62°C, and the reaction time is 12-18h; preferably, the reaction temperature is 60°C for 12h.

[0015] According to a preferred embodiment of the present invention, in step S4, before adding iodine granules and hypophosphite, an equal volume of toluene to glacial acetic acid is added to the reaction solution obtained in step S3, so that toluene and glacial acetic acid form a mixed solvent system. This operation can significantly improve the efficiency and effect of the reaction, thereby improving the synthesis yield and product purity of 4,4'-bis[cyclo[4.2.0]oct-1(6),2,4-trien-3-ylmethyl]-1,1'-biphenyl. Experiments show that when acetic acid and toluene are added in equal volumes, the product purity and yield are better.

[0016] According to a preferred embodiment of the present invention, in S4, the separation and purification method is as follows: the reaction solution is concentrated by rotary evaporation at a temperature not exceeding 40°C to obtain a viscous substance; the viscous substance is added to an appropriate amount of toluene and dissolved at a temperature not exceeding 40°C; after mixing with silica gel, it is evaporated to dryness at a temperature ≤40°C; the compound is loaded onto silica gel and packed into the top of a chromatography column; then, eluent is added for column elution to obtain the target product. The entire separation and purification process is controlled at ≤40°C to protect the target product and avoid the easy ring-opening of the benzocyclobutene structure at high temperatures; the eluent is a weakly polar elution system, such as a mixture of petroleum ether and ethyl acetate in a volume ratio of (15-20):1, or a mixture of n-hexane and ethyl acetate in a volume ratio of (15-20):1, or a mixture of toluene and ethyl acetate in a volume ratio of (20-30):1.

[0017] The preparation method of the present invention involves generating a Grignard reagent in S1, and the reaction process from S2 to S4 is as follows: .

[0018] (III) Beneficial Effects The method for preparing 4,4'-bis[cyclo[4.2.0]oct-1(6),2,4-trien-3-ylmethyl]-1,1'-biphenyl of this application, through a continuous reaction process of Grignardization, coupling, solvent displacement and reduction, achieves efficient preparation of the target product and has the following significant technical advantages compared with the prior art: (1) The reaction process is simple and controllable, realizing efficient one-pot synthesis: This application uses Br-BCB as raw material. After obtaining the Grignard reagent intermediate through Grignard reaction, it directly undergoes a coupling reaction with 4,4'-biphenyldicarboxaldehyde. Subsequently, the target product solution can be obtained by solvent replacement with glacial acetic acid and reduction with iodine granules and hypophosphite. The reaction system does not need to be changed throughout the process, and the synthesis is completed in one pot. The process parameters of each reaction step are clear, the operation process is simple, the reaction process is stable and reliable, easy to control, and the yield can reach more than 40%, which is higher than the yield of traditional synthesis routes and is suitable for large-scale industrial production.

[0019] (2) Mild reaction conditions reduce production operation requirements: The Grignification, coupling and reduction reactions of this application are all carried out at medium and low temperature conventional reaction temperatures, without the need for harsh reaction conditions such as high temperature and high pressure. The requirements for production equipment are low, which greatly reduces the difficulty of operation and process control costs in the production process, reduces the probability of the product undergoing ring-opening reaction with other substances due to its high activity, and reduces by-products.

[0020] (3) Excellent product purity and yield, improving purification difficulties: In the preferred embodiment of the present invention, by optimizing the solvent system of equal volume mixing of glacial acetic acid and toluene, and by precisely controlling the key process parameters of each reaction step, the occurrence of side reactions is effectively reduced. The purity of the obtained 4,4'-di[cyclo[4.2.0]oct-1(6),2,4-trien-3-ylmethyl]-1,1'-biphenyl product can reach more than 99%, which significantly improves the technical status quo of difficult product purification and low purity in the existing preparation method; at the same time, the utilization rate of reaction raw materials is high, the product yield is significantly improved, and it has good industrial production economy.

[0021] (4) The product has high application value and breaks through the bottleneck of electronic material manufacturing: The 4,4'-di[cyclo[4.2.0]octyl-1(6),2,4-trien-3-ylmethyl]-1,1'-biphenyl synthesized in this application can be used as a polymer monomer for a new type of photoelectric anti-corrosion dry film. It is suitable for the modification and preparation of photoelectric anti-corrosion dry film. Its excellent structural characteristics can improve the comprehensive performance of photoelectric anti-corrosion dry film, providing high-quality raw materials for the research and development and production of electronic materials. It is conducive to breaking through the technical bottleneck in the existing electronic material manufacturing field and meeting the demand for high-end electronic materials in emerging fields such as 5G communication, Internet of Things, and integrated circuit chip packaging. Attached Figure Description

[0022] Figure 1 The NMR spectrum of 4,4'-bis[cyclo[4.2.0]octyl-1(6),2,4-trien-3-ylmethyl]-1,1'-biphenyl synthesized in Example 1 is shown. Detailed Implementation

[0023] To better explain and facilitate understanding of the present invention, the present invention will be described in detail below with reference to the accompanying drawings and specific embodiments.

[0024] This application uses Br-BCB as a raw material. After Grignardization, it reacts with 4,4'-biphenyldicarboxaldehyde. The reaction solution is solvent-replaced with glacial acetic acid, and then reduced with iodine granules and hypophosphite to obtain a solution containing the target product. After separation, purification, and evaporation, 4,4'-bis[cyclo[4.2.0]oct-1(6),2,4-trien-3-ylmethyl]-1,1'-biphenyl is obtained. All raw materials used in this application are commercially available products. The absence of a manufacturer indicates that they can be obtained through conventional commercial channels. Br-BCB is an abbreviation for 4-bromobenzocyclobutene, with the following chemical structure: .

[0025] This method uses 3-bromobenzocyclobutene (Br-BCB) and 4,4'-biphenyldicarboxaldehyde as core raw materials, and achieves the efficient preparation of 4,4'-bis[cyclo[4.2.0]oct-1(6),2,4-trien-3-ylmethyl]-1,1'-biphenyl through a five-step process: Grignardization reaction, coupling reaction, solvent displacement quenching, reduction reaction, and separation and purification. The reaction conditions are mild and the process is controllable throughout, and the purity of the obtained product can reach over 99%, with excellent yield. It is suitable for laboratory preparation and large-scale industrial production.

[0026] The method for preparing 4,4'-bi[cyclo[4.2.0]oct-1(6),2,4-trien-3-ylmethyl]-1,1'-biphenyl provided by this invention includes the following specific preparation steps: S1: Grignification reaction to prepare aryl Grignard reagent intermediates (1) Raw materials and solvents: Dissolve Br-BCB in a cyclic ether organic solvent suitable for Grignardization reaction, and add magnesium filings (Mg) and initiator; tetrahydrofuran (THF) is preferred as solvent, but 2-methyltetrahydrofuran can also be used; solvents containing active hydrogen, polar unsaturated bonds, or functional groups that are easily attacked by nucleophiles (such as alcohols, carboxylic acids, amines, esters, dichloromethane (DCM), etc.) are strictly prohibited.

[0027] (2) Process parameters Material ratio: The molar ratio of Br-BCB to magnesium chips is 1:1.3-1.7, preferably 1:1.5, and the concentration of Br-BCB in THF is 0.5M. Too low a dosage of magnesium chips (less than 1.3 times the molar amount of Br-BCB) will result in insufficient Br-BCB conversion, while too high a dosage (more than 1.7 times the molar amount of Br-BCB) will lead to raw material waste without significant synergistic effect. In the examples, the dosage of magnesium chips was 1.1, 1.3, 1.5, 1.7, and 2.0 times the molar amount of Br-BCB, respectively. Ultimately, experimental results showed that when the dosage of magnesium chips was 1.5 times the molar amount of Br-BCB, the purity and yield of the obtained product were superior.

[0028] Reaction conditions: The reaction was carried out under anhydrous and oxygen-free conditions, using an oil bath for heating (to isolate water vapor and avoid interference from water vapor generated by the water bath); when the solvent was THF, the reaction temperature was 45-60℃, preferably 55℃, and the reaction time was 1-2 hours, preferably maintaining the temperature for 0.5-0.6 hours after the reaction solution stopped boiling. In the examples, the reaction temperatures were set to 45℃, 50℃, 55℃, and 60℃, and the oil temperature was 55-60℃. Finally, the experimental results showed that a reaction temperature of 55℃ and a reaction time of 1 hour were more conducive to the smooth progress of the reaction, and the purity and yield of the obtained product were better.

[0029] Initiator: Select at least one of bromoethane, dibromoethane, and 1,2-dibromoethane, in an amount of 5-10 wt% of the mass of Br-BCB.

[0030] (3) Reaction product: Br-BCB undergoes a Grignification reaction with magnesium shavings, breaking the C-Br bond to generate 4-benzocyclobutenyl magnesium bromide (BCB-Mg Br) aryl Grignard reagent intermediate, which provides an active site for subsequent coupling reactions.

[0031] S2: Coupling reaction with 4,4'-biphenyldialdehyde (1) Pre-treatment: Cool the Grignard reagent reaction solution obtained from S1 to 10-30℃ to avoid the side reaction from being aggravated during subsequent drop addition due to high temperature.

[0032] (2) Droplet addition reaction: Add a solution containing 4,4'-biphenyldicarboxaldehyde dropwise to the cooled reaction solution. When adding the solution, control the temperature rise of the system to not exceed 5°C (the highest temperature of the system is ≤35°C to reduce the side reactions between the solvent and the remaining Grignard reagent), and stir thoroughly. After the addition is completed, continue stirring for at least 1 hour to ensure that the coupling reaction proceeds fully.

[0033] (3) Process parameters Material ratio: The molar ratio of 4,4'-biphenyldicarboxaldehyde to Br-BCB is 1:2.2-2.8, preferably 1:2.5. A ratio lower than 1:2.2 results in incomplete reaction, while a ratio higher than 1:2.8 easily leads to waste of raw materials, increases side reactions, increases separation difficulty, and reduces product purity. In the examples, the molar ratio of 4,4'-biphenyldicarboxaldehyde to Br-BCB can be set to 1:2.5, 1:2.2, and 1:2.8; experimental results show that when the molar ratio of 4,4'-biphenyldicarboxaldehyde to Br-BCB is 1:2.5, the reaction proceeds more completely, and the purity and yield of the obtained product are better.

[0034] Raw material solvent: The solvent for dissolving 4,4'-biphenyldicarboxaldehyde is at least one of DCM and THF; both have low boiling points (DCM: 39.8℃, THF: 66℃), are easy to remove in subsequent steps, and do not undergo side reactions with Grignard reagents or reaction intermediates at ≤35℃, ensuring the stability of the system.

[0035] (4) Reaction principle: The aryl magnesium end of the Grignard reagent intermediate acts as a strong nucleophilic group, which attacks the aldehyde group (-CHO) in the 4,4'-biphenyl dicarboxaldehyde molecule, and undergoes a nucleophilic addition reaction to form a hydroxyl-containing aryl addition intermediate, thus completing the initial connection between biphenyl and benzocyclobutene skeleton.

[0036] S3: Quenching with glacial acetic acid and solvent replacement (1) Quenching and dissolving: Add glacial acetic acid to the coupling reaction solution of S2. The ratio of the volume of glacial acetic acid added to the volume of the S2 reaction solution is 1-1.2:1, so as to better dissolve the reaction solution and replace the low-boiling-point solvent introduced in the previous step. Glacial acetic acid quenches the excess Grignard reagent in the system (neutralizes the strongly basic system), so that the reaction changes from strongly basic to weakly acidic. On the other hand, it dissolves the reaction intermediate and avoids agglomeration.

[0037] (2) Rotary evaporation to remove low-boiling-point solvents: The reaction solution after treatment with glacial acetic acid is subjected to rotary evaporation to remove solvents with boiling points lower than glacial acetic acid (mainly low-boiling-point solvents introduced in the previous steps such as THF and DCM); the boiling temperature of the remaining reaction solution is controlled at 60-95℃ (far lower than the boiling point of glacial acetic acid 117.9℃) to ensure that glacial acetic acid is not removed and only the low-boiling-point solvents are completely replaced; negative pressure rotary evaporation can be used to reduce the rotary evaporation temperature (e.g., 60℃) to reduce the risk of intermediate heating.

[0038] (3) Treatment of rotary evaporation byproducts: The solvent vapor distilled by rotary evaporation is cooled and then recycled to achieve solvent recycling and reduce costs.

[0039] (4) System results: After rotary evaporation, the system uses glacial acetic acid as the only main solvent, forming a stable weakly acidic environment, which provides a suitable reaction medium for the subsequent reduction reaction.

[0040] S4: Reduction reaction and separation / purification (a) Reduction reaction (1) Solvent system optimization: To the glacial acetic acid reaction solution obtained in S3, an equal volume of toluene was added to construct a glacial acetic acid-toluene mixed solvent system. Glacial acetic acid alone cannot meet the requirements of the reduction reaction. Toluene is an inert aromatic hydrocarbon solvent (without active hydrogen and polar unsaturated bonds) and does not participate in the reduction reaction. The optimal ratio is to mix the two in equal volumes (too much or too little toluene will lead to a significant decrease in product yield and purity). In the comparative examples, the toluene content was set to 1 / 2, 2 times, or no toluene, and the product yield and purity all decreased significantly. However, when equal volumes of acetic acid and toluene were added, the product purity and yield were better.

[0041] (2) Reduction reaction feeding: Iodine granules and hypophosphite are added to the mixed solvent system to carry out the reduction reaction; the molar ratio of 4,4'-biphenyldicarboxaldehyde, iodine granules and hypophosphite is 1:0.3-0.5:1.5-4, preferably 1:0.4:3.

[0042] (3) Low temperature reaction conditions: The reduction reaction temperature is controlled at 55-62℃, preferably 60℃, and the reaction time is 12-18h, preferably 12h. Under these conditions, the reduction reaction efficiency is the highest and the ring-opening of the benzocyclobutene structure can be avoided by heating.

[0043] (4) Reaction principle: hypophosphite is the core reducing agent and iodine granules are the reducing aid. The two work together to reduce the hydroxyl intermediate generated by S2 coupling to methylene (-CH2-), and finally form the target product 4,4'-bi[cyclo[4.2.0]oct-1(6),2,4-trien-3-ylmethyl]-1,1'-biphenyl.

[0044] (5) The core role of the glacial acetic acid-toluene mixed solvent system ① Improve solubility: Glacial acetic acid dissolves hypophosphite, toluene dissolves aryl intermediates and disperses iodine particles, achieving homogeneous dissolution of all components in the reaction system and avoiding incomplete reaction caused by raw material agglomeration; ②Regulate the reaction rate: Dilute the concentration of glacial acetic acid to moderately reduce the protonation ability of the system, break the hydrogen bond binding between glacial acetic acid and hypophosphite, and restore the optimal reducing activity of hypophosphite; ③ Reduce system viscosity: Improve the fluidity and mass transfer efficiency of the reaction system, avoid side reactions such as self-polymerization and ring-opening caused by the local aggregation of aryl intermediates, and ensure product purity; ④ Adapting to subsequent separation: Toluene is well miscible with column chromatography eluent, eliminating the need for additional solvent replacement. Sample loading and separation can be performed directly by rotary evaporation, improving process efficiency.

[0045] (II) Separation and purification The temperature was controlled at ≤40℃ throughout the separation and purification process to avoid ring-opening reaction of the benzocyclobutene structure in the target product due to high temperature. The specific steps are as follows: (1) Rotary evaporation concentration: The reduction reaction solution is concentrated by rotary evaporation to remove part of the solvent and obtain a viscous substance containing the target product.

[0046] (2) Silica gel sample mixing: Dissolve the viscous substance in an appropriate amount of toluene, add 200-300 mesh thin-layer chromatography silica gel and stir thoroughly. Then evaporate the toluene again by rotary evaporation to ensure that the target product is uniformly loaded on the surface and pores of the silica gel particles (pretreatment before dry loading). (3) Column chromatography separation: The silica gel loaded with the product is loaded into the top of the chromatography column, and a weakly polar elution system is added for column elution. The separation is achieved by utilizing the difference in adsorption / desorption capacity of the target product and the byproduct on the silica gel. (4) Fraction collection and purification: The eluted fraction was detected by thin-layer chromatography (TLC), and the fraction containing the pure target product was collected. The eluent was removed by rotary evaporation to obtain high-purity 4,4'-bis[cyclo[4.2.0]oct-1(6),2,4-trien-3-ylmethyl]-1,1'-biphenyl.

[0047] (5) Optimize the elution system (all are volume ratios, sorted by separation effect / process compatibility) Petroleum ether (60-90℃):ethyl acetate = (15-20):1 (optimal, good separation effect, low cost, and strong industrial applicability); hexane: ethyl acetate = (15-20): 1 (for high-purity applications, free from petroleum ether peak interference). Toluene:ethyl acetate = (20-30):1 (seamless connection with the preceding toluene solvent, avoiding sample precipitation and column blockage).

[0048] In the preparation method of this invention, the Grignardization reaction of S1 must be carried out under anhydrous and oxygen-free conditions: the Grignard reagent (BCB-MgBr) is chemically reactive and decomposes rapidly upon contact with water and oxygen (forming benzocyclobutene upon contact with water and peroxide upon contact with oxygen). Therefore, water and oxygen must be strictly isolated throughout the reaction, and oil bath heating is the preferred method. The key to the coupling reaction of S2 is temperature control: the nucleophilic addition reaction between the Grignard reagent and the aldehyde group is an exothermic reaction. If the temperature is too high (>35°C) during dropwise addition, the remaining Grignard reagent will undergo side reactions with DCM / THF, and may also lead to the decomposition of intermediates. Therefore, the temperature rise and the maximum temperature of the system must be strictly controlled. The core purpose of solvent replacement in S3 is to remove low-boiling-point solvent impurities from the previous steps to avoid interference with the reduction reaction. At the same time, excess Grignard reagent is quenched by glacial acetic acid to adjust the system to a weakly acidic state, which is suitable for the medium requirements of the reduction reaction. In step S4, the reduction reaction is carried out at medium and low temperatures, and the reducing agents are iodine granules and hypophosphite. The crude target product is a viscous substance, and direct wet loading can easily lead to column blockage, uneven sample distribution, and poor separation. After mixing with silica gel, the product is uniformly loaded onto the silica gel, resulting in smooth column flow, good separation, reduced product adsorption loss, and improved yield.

[0049] The following description is based on preferred embodiments and comparative examples of the present invention.

[0050] Example 1.1 The preparation method of 4,4'-bis[cyclo[4.2.0]oct-1(6),2,4-trien-3-ylmethyl]-1,1'-biphenyl in this embodiment is as follows: S1 Grignardization reaction: 1.83 g Br-BCB (10 mmol), 0.36 g magnesium shavings (15 mmol), 0.09 g 1,2-dibromoethane (initiator is 5% of the mass of Br-BCB), and 20 mL of THF with a water content of less than 0.05% (w / w) were added to a three-necked flask equipped with a thermometer, a straight condenser, and a magnetic stirrer. The mixture was heated in an oil bath to 55 °C for 1 h, and after boiling was stopped, it was kept at this temperature for 0.5 h to generate the Grignard reagent intermediate. S2 coupling reaction: Cool the reaction solution of S1 to 30℃, dissolve 0.84g of 4,4'-biphenyldicarboxaldehyde (4mmol) in 20mL of DCM, and slowly add it dropwise while the system temperature does not exceed 35℃, stirring thoroughly during the addition. After the addition is completed, continue stirring for 2h. S3 Quenching and Solvent Removal: Add 40 mL of glacial acetic acid to the reaction solution of S2, and evaporate low-boiling-point solvents such as DCM and THF at 30°C. Control the boiling temperature of the remaining reaction solution to reach above 60°C.

[0051] S4 reduction reaction: Add 40 mL of toluene to the reaction solution of S3, then add 0.41 g of iodine granules (1.6 mmol) and hypophosphite aqueous solution (containing 12 mmol of hypophosphite, and the molar ratio of 4,4'-biphenyldicarboxaldehyde, iodine granules and hypophosphite is 1:0.4:3), raise the temperature of the system to 60 °C and stir the reaction for 12 h.

[0052] S5 Separation and Purification: The reaction solution of S4 was evaporated to dryness at 40℃. The resulting viscous substance was dissolved in an appropriate amount of toluene at 40℃, mixed with silica gel, and evaporated to dryness again at 40℃. The compound was loaded onto silica gel and packed into the top of a chromatography column. Elution buffer was added for column elution. The eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of (15-20):1. The target product 4,4'-bis[cyclo[4.2.0]oct-1(6),2,4-trien-3-ylmethyl]-1,1'-biphenyl was obtained. The NMR spectrum detection results of the product are as follows. Figure 1 As shown.

[0053] Example 1.2 The only difference between this embodiment and Example 1.1 is that in S1, the molar ratio of 4,4'-biphenyldicarboxaldehyde to Br-BCB is 1:2.2, that is, 4.55 mmol of 4,4'-biphenyldicarboxaldehyde and 1.83 g of Br-BCB (10 mmol) are added. The rest of the steps are exactly the same as in Example 1.1.

[0054] Example 1.3 The only difference between this embodiment and Example 1.1 is that in S1, the molar ratio of 4,4'-biphenyldicarboxaldehyde to Br-BCB is 1:2.8, that is, 3.57 mmol of 4,4'-biphenyldicarboxaldehyde and 1.83 g of Br-BCB (10 mmol) are added. The rest of the steps are exactly the same as in Example 1.1.

[0055] Example 2.1 The only difference between this embodiment and Example 1.1 is that in S1, the amount of 1,2-dibromoethane used is 10% of the mass of Br-BCB, that is, 0.18g of 1,2-dibromoethane is added. The remaining steps are exactly the same as in Example 1.1.

[0056] Example 2.2 The only difference between this embodiment and Example 1.1 is that in S1, the initiator is bromoethane, and the amount used is 5% of the mass of Br-BCB. The remaining steps are exactly the same as in Example 1.1.

[0057] Example 2.3 The only difference between this embodiment and Example 1.1 is that in S1, the initiator is bromoethane, and the amount used is 10% of the mass of Br-BCB. The remaining steps are exactly the same as in Example 1.1.

[0058] Example 3.1 The only difference between this embodiment and Embodiment 1.1 is that in S4, the amount of iodine granules used is 0.3 times the molar amount of 4,4'-biphenyldicarboxaldehyde, that is, 0.31g of iodine granules are added. The remaining steps are exactly the same as in Embodiment 1.1.

[0059] Example 3.2 The only difference between this embodiment and Embodiment 1.1 is that in S4, the amount of iodine granules used is 0.5 times the molar amount of 4,4'-biphenyldicarboxaldehyde, that is, 0.51g of iodine granules are added. The remaining steps are exactly the same as in Embodiment 1.1.

[0060] Example 4.1 The only difference between this embodiment and Embodiment 1.1 is that the oil bath temperature in S1 is 45°C; the remaining steps are exactly the same as in Embodiment 1.1.

[0061] Example 4.2 The only difference between this embodiment and embodiment 1.1 is that the oil bath temperature in S1 is 50°C, while the rest of the steps are exactly the same as in embodiment 1.1.

[0062] Example 4.3 The only difference between this embodiment and embodiment 1.1 is that the oil bath temperature in S1 is 60°C, while the rest of the steps are exactly the same as in embodiment 1.1.

[0063] Comparative Example 1.1 The only difference between this comparative example and Example 1.1 is that in S2, the molar ratio of 4,4'-biphenyldicarboxaldehyde to Br-BCB is 1:2, that is, 5 mmol of 4,4'-biphenyldicarboxaldehyde and 1.83 g of Br-BCB (10 mmol) are added. The rest of the steps are exactly the same as in Example 1.1.

[0064] Comparative Example 1.2 The only difference between this comparative example and Example 1.1 is that in S2, the molar ratio of 4,4'-biphenyldicarboxaldehyde to Br-BCB is 1:3, that is, 3.3 mmol of 4,4'-biphenyldicarboxaldehyde and 1.83 g of Br-BCB (10 mmol) are added. The rest of the steps are exactly the same as in Example 1.1.

[0065] Comparative Example 2.1 The only difference between this comparative example and Example 1.1 is that in S4, the amount of iodine granules used is 0.2 times the molar amount of 4,4'-biphenyldicarboxaldehyde, that is, 0.21g of iodine granules are added. The remaining steps are exactly the same as in Example 1.1.

[0066] Comparative Example 2.2 The only difference between this comparative example and Example 1.1 is that in S4, the amount of iodine granules used is 0.6 times the molar amount of 4,4'-biphenyldicarboxaldehyde, that is, 0.61g of iodine granules are added. The remaining steps are exactly the same as in Example 1.1.

[0067] Comparative Example 3.1 The only difference between this comparative example and Example 1.1 is that in S4, the amount of toluene used is 1 / 2 the volume of glacial acetic acid; the rest of the steps are exactly the same as in Example 1.1.

[0068] Comparative Example 3.2 The only difference between this comparative example and Example 1.1 is that the amount of toluene used in S4 is twice the volume of glacial acetic acid; the rest of the steps are exactly the same as in Example 1.1.

[0069] Comparative Example 3.3 The only difference between this comparative example and Example 1.1 is that in S4, toluene was not added before the iodine granules were added (so that glacial acetic acid-toluene complex solvent was not formed), and the rest of the steps are exactly the same as in Example 1.1.

[0070] The product yield and purity test results of the above embodiments and comparative examples are shown in Table 1: Table 1: Product yields and purity of each example and comparative example

[0071] The following conclusions can be drawn from the above results: Effect of raw material ratio: The molar ratio of 4,4'-biphenyldicarboxaldehyde to Br-BCB is feasible in the range of 2.2-2.8, while the yield and purity of the product are optimal at 1:2.5 (Example 1.1); when the ratio deviates from this value, such as in Comparative Examples 1.1 and 1.2, the yield and purity decrease.

[0072] Effect of initiator: The type and amount of initiator have minimal effect on product yield and purity. When the initiator is 1,2-dibromoethane or bromoethane, it can promote the Grignardization reaction.

[0073] Effect of iodine granule dosage: Iodine granules are a key auxiliary agent in the reduction reaction. A dosage of 0.3-0.5 times the molar amount of 4,4'-biphenyldicarboxaldehyde is acceptable, with 0.4 times yielding the best results. Insufficient dosage leads to incomplete reaction (Comparative Example 2.1), while excessive dosage triggers side reactions and reduces purity (Comparative Example 2.2). In Example 3.1, insufficient iodine granule dosage resulted in a significant decrease in yield, but the product purity was very high. Although Comparative Example 2.1 increased the iodine granule dosage, the yield did not significantly improve compared to Example 1.1, indicating that the positive effect of iodine granule dosage on yield has reached its boundary effect.

[0074] Effect of reaction temperature: The product yield and purity are optimal when the Grignardization reaction temperature is 55°C (as in Example 1.1); if the temperature is too low, the reaction rate is slow and the conversion rate is low (Example 4.1); if the temperature is too high, the system will boil violently, affecting the reaction stability (Example 4.3).

[0075] Effect of solvent system: When glacial acetic acid and toluene are mixed in equal volumes as solvents for the reduction reaction, the system has the best solubility and reaction rate. Too little or too much toluene will reduce the yield (as in Comparative Examples 3.1 and 3.2). Without the addition of toluene, the reaction is difficult to proceed fully and the yield drops significantly (as in Comparative Example 3.3).

[0076] In summary, this application has achieved efficient and high-purity synthesis of 4,4'-bis[cyclo[4.2.0]oct-1(6),2,4-trien-3-ylmethyl]-1,1'-biphenyl by optimizing the process parameters of each reaction step. The process is simple and the conditions are mild, which has good prospects for industrial application.

[0077] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features. These modifications or substitutions, or combinations of technical features in the above embodiments that do not conflict with each other, can be made in accordance with the manner described in the embodiments. These modifications, substitutions or combinations do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing 4,4'-bis[cyclo[4.2.0]oct-1(6),2,4-trien-3-ylmethyl]-1,1'-biphenyl, characterized in that, Includes the following steps: S1. Dissolve 4-bromobenzocyclobutene (Br-BCB) in an organic solvent suitable for Grignardization, add magnesium shavings and an initiator, and heat to carry out the Grignardization reaction. The reaction is carried out under anhydrous and oxygen-free conditions, and an intermediate is generated after the reaction. S2. Cool the reaction solution of S1 to 10-30℃, and add a solution containing 4,4'-biphenyldicarboxaldehyde dropwise to carry out the coupling reaction. When adding dropwise, control the temperature rise of the system to not exceed 5℃ (the system temperature should not exceed 35℃ to reduce the side reaction between the solvent and the remaining Grignard reagent) and stir thoroughly. After the dropwise addition is completed, continue stirring for at least 1 hour. S3. Add glacial acetic acid to the reaction solution of S2 to quench and dissolve the reaction solution, and remove the solvent with a boiling point lower than glacial acetic acid by rotary evaporation. S4. Iodine granules and hypophosphite were added to the reaction solution of S3 to carry out a reduction reaction to generate the target product. After separation and purification, 4,4'-bis[cyclo[4.2.0]octyl-1(6),2,4-trien-3-ylmethyl]-1,1'-biphenyl was obtained.

2. The preparation method according to claim 1, characterized in that, In S1, the organic solvent is tetrahydrofuran, the reaction temperature is 45-60℃, the reaction process is carried out by oil bath heating, and the reaction time is 1-2 hours.

3. The preparation method according to claim 2, characterized in that, In S1, the molar ratio of Br-BCB to magnesium shavings is 1:1.3-1.7, and the concentration of Br-BCB in THF is 0.5M.

4. The preparation method according to claim 2 or 3, characterized in that, In S1, the reaction temperature is 55℃ and the reaction time is 1h.

5. The preparation method according to claim 1, characterized in that, In S1, the initiator is at least one of bromoethane, dibromoethane, or 1,2-dibromoethane, and the amount of initiator used is 5-10% of the mass of Br-BCB; the solvent of the solution containing 4,4'-biphenyldicarboxaldehyde is at least one of dichloromethane (DCM) and THF.

6. The preparation method according to claim 1, characterized in that, In S2, the molar ratio of 4,4'-biphenyldicarboxaldehyde to Br-BCB is 1:2.2-2.

8.

7. The preparation method according to claim 1, characterized in that, In step S3, the volume ratio of the added glacial acetic acid to the volume of the reaction solution obtained in step S2 is 1-1.2:1, and the boiling temperature of the remaining reaction solution is controlled at 60℃-95℃ during rotary evaporation; or, negative pressure is applied during rotary evaporation to promote volatilization and the rotary evaporation temperature is lowered within the range of 60℃-95℃ under negative pressure. The rotary evaporation process also includes cooling and recovering the vapors of the removed low-boiling-point organic solvents.

8. The preparation method according to claim 1, characterized in that, In S4, the molar ratio of 4,4'-biphenyldicarboxaldehyde, iodine granules, and hypophosphite is 1:0.3-0.5:1.5-4; the reduction reaction temperature is 55-62℃, and the reaction time is 12-18h.

9. The preparation method according to claim 1, characterized in that, In step S4, before adding iodine granules and hypophosphite, toluene of the same volume as glacial acetic acid is added to the reaction solution obtained in step S3, so that toluene and glacial acetic acid form a mixed solvent system.

10. The preparation method according to claim 1, characterized in that, In S4, the separation and purification method is as follows: the reaction solution is concentrated by rotary evaporation to obtain a viscous substance, the viscous substance is added to an appropriate amount of toluene and dissolved, mixed with silica gel and then evaporated to dryness, the compound is loaded onto silica gel, packed into the top of the chromatography column, and then eluent is added for column elution to obtain the target product; the entire separation and purification process is controlled at ≤40℃; the eluent is a weakly polar elution system.

Images